Composition, system, and method for modulating release kinetics in implantable drug delivery devices by modifying drug solubility

ABSTRACT

An implantable drug delivery device loaded with a beneficial agent is provided, wherein the beneficial agent is in two different forms, a first form having a higher solubility and a second form having a lower solubility, and wherein the two different forms are present in a proportion which is selected to achieve a desired release rate.

This application claims priority under 35 U.S.C. § 119 to U.S.provisional patent application No. 60/716,568, filed 12 Sep. 2005, theentirety of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to devices, systems, and processes usefulas implantable delivery device, and more specifically to an implantabledelivery device which can deliver a drug to a body in two forms havingdifferent solubilities for the purpose selecting a desirable releaserate.

2. Brief Description of the Related Art

In the area of local drug delivery, such as in drug eluting stents andother implantable drug delivery devices, the control of release kineticsis important to achieving the desired clinical results. For example, itis often desirable to deliver a drug locally over time periods of days,weeks, or longer. It has been found that highly water soluble drugs whencoated onto a stent or other implantable device with or without apolymer will be released very fast due to the high water solubility ofthe drug. Less water soluble drugs are released at a slower rate fromsimilar systems. Often this slower rate is more desirable for localsustained release applications.

The slow or sustained release used in local delivery is generally justthe opposite of the desirable release for systemic delivery of a drug byan oral tablet or capsule which requires high water solubility and quickrelease in a matter of minutes or hours. Accordingly, when a drugintended for oral or other systemic delivery is adapted for localdelivery in an implantable medical device, it may be desirable to alterthe drug form to achieve a lower solubility and a slower and moresustained release for delivery over many hours and preferably days.

In local drug delivery, either solely the salt (ionic) form of the drugor solely the purely neutral form are delivered. The rate of drugdelivery is controlled by the choice of excipient or matrix, but not bythe form of the drug. One example of this is in drug eluting stentswhere the polymer matrices containing the drug are chosen to achieve thedesired release kinetic. This often means that non-biodegradablehydrophobic polymers are used to control and slow down the release ofthe drug.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, an implantable drugdelivery device is provided comprising an implantable device configuredto be implanted within tissue, lumens, organs of the body; a beneficialagent provided in or on the implantable medical device for delivery tothe tissue, lumen, or organ of the body to achieve a desired beneficialeffect; wherein the beneficial agent is provided in two different forms,a first form having a higher solubility and a second form having a lowersolubility, and wherein the two different forms are present in aproportion which is selected to achieve a desired release rate.

According to another aspect of the present invention, a method offorming an implantable drug delivery device is provided comprisingselecting an implantable device configured to be implanted withintissue, lumens, or organs of the body; providing a beneficial agent intwo different forms, a first form having a higher solubility and asecond form having a lower solubility; selecting a proportion of the twodifferent forms to achieve a desired release rate; and affixing thebeneficial agent in the two different forms of the beneficial agent andin the selected proportion to the implantable device.

Still other aspects, features, and attendant advantages of the presentinvention will become apparent to those skilled in the art from areading of the following detailed description of embodiments constructedin accordance therewith, taken in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention of the present application will now be described in moredetail with reference to exemplary embodiments of the apparatus andmethod, given only by way of example, and with reference to theaccompanying drawings, in which:

FIG. 1 is a graph of the cumulative release from low dose imatinibstents having different proportions of imatinib mesylate salt andimatinib free-base. The total drug load was 160 μg.

FIG. 2 is a graph of the cumulative release from high dose imatinibstents having different proportions of imatinib mesylate salt andimatinib free-base. The total drug load was 270 μg.

FIG. 3 is a graph of the solubility of paclitaxel formulated withdifferent amounts of the solubilization agent Tween.

FIG. 4 is a graph of the effect of various counter ions on the in vitrorelease of the salt form of imatinib.

FIG. 5 is a graph of the release rates from imatinib stents havingdifferent molar ratios of imatinib and its salt.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The terms “agent” or “beneficial agent” as used herein are intended tohave the broadest possible interpretation and are used to include anytherapeutic agent or drug, as well as inactive agents such as barrierlayers, carrier layers, therapeutic layers, or protective layers.

The terms “drug” and “therapeutic agent” are used interchangeably torefer to any therapeutically active substance that is delivered to abodily lumen of a living being to produce a desired, usually beneficial,effect. Beneficial agents may include one or more drug or therapeuticagent.

The terms “openings” and “holes” includes both through openings andrecesses.

The term “polymer” refers to molecules formed from the chemical union oftwo or more repeating units, called monomers. Accordingly, includedwithin the term “polymer” may be, for example, dimers, trimers andoligomers. The polymer may be synthetic, naturally-occurring orsemisynthetic. In preferred form, the term “polymer” refers to moleculeswhich typically have a Mw greater than about 3000 and preferably greaterthan about 10,000 and a Mw that is less than about 10 million,preferably less than about a million and more preferably less than about200,000. Examples of polymers include but are not limited to,poly-α-hydroxy acid esters such as, polylactic acid (PLLA or DLPLA),polyglycolic acid, polylactic-co-glycolic acid (PLGA), polylacticacid-co-caprolactone; poly (ester-co-amide) copolymers;poly(block-ethylene oxide-block-lactide-co-glycolide) polymers(PEO-block-PLGA and PEO-block-PLGA-block-PEO); polyethylene glycol andpolyethylene oxide, poly(block-ethylene oxide-block-propyleneoxide-block-ethylene oxide); polyvinyl pyrrolidone; polyorthoesters;polysaccharides and polysaccharide derivatives such as polyhyaluronicacid, poly(glucose), polyalginic acid, chitin, chitosan, chitosanderivatives, cellulose, methyl cellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose, cyclodextrins andsubstituted cyclodextrins, such as beta-cyclodextrin sulfobutyl ethers;polypeptides and proteins, such as polylysine, polyglutamic acid,albumin; polyanhydrides; polyhydroxy alkonoates such as polyhydroxyvalerate, polyhydroxy butyrate, and the like.

The term “primarily” with respect to directional delivery, refers to anamount greater than about 50% of the total amount of therapeutic agentprovided to a blood vessel is provided in the primary direction.

Water soluble forms of a drug will elute faster than less water solubleforms of the same drug. The invention involves modulating the rate oflocal in vivo delivery of a drug substance that is capable of existingin a first less water soluble form and a second more water soluble form.The release rate is modulated by controlling the relative proportion ofa more slowly eluting form to a more rapidly eluting form in the overalldose to be delivered. Control of the water solubility of the agent to bedelivered can be achieved in a number of ways, some of which will bedescribed herein. The multiple forms of the same drug which can becreated each with different solubilities are used together.

When a specific release kinetic is desired for local delivery, two ormore forms of the drug with different solubilities can be combined in aproportion which is selected to achieve the desired release kineticprofile.

Modifying the Ionic/Neutral Form

A first method to modulate the rate of drug release, or elution, from adevice is to control the proportion of a more water soluble ionic orsalt form of a drug to a less water soluble neutral form of the drugcontained on or within the device, such as a stent.

To be effectively delivered orally, many drugs must be converted from aneutral, non-ionic form (for example, a free base form) to a more watersoluble ionic form (for example, a salt). For drugs containing what aregenerally called basic functional groups, this can be accomplished bycreating the ionic salt form by addition of an acid sufficiently strongto protonate the basic moiety. For drugs that contain what are generallycalled acidic functional groups, this can be accomplished by creatingthe ionic salt form by addition of a base sufficiently strong tode-protonate the acidic functionality to produce the so-called conjugatebase form. Although this approach is optimal for oral delivery, in thecase of local delivery, the rate of elution of the purely ionic form ofthe drug can be more rapid than desired for a sustained delivery system.

The ionic form of a molecule (including a drug molecule) will be morewater soluble than the non-ionic form; the in vivo elution rate isrelated to the water solubility. Consequently, by the method of thisinvention, the rate of elution of the drug from the local deliverydevice may be modulated by specifying the relative proportion of ionicand non-ionic forms of the drug in the total drug loaded on the localdelivery device.

Generally, the rate of delivery of the ionic, salt form of many drugs istoo rapid to provide a desirable “sustained delivery” system. It isenvisioned that by converting a portion or all of a drug into its freebase form, the rate of delivery will be decreased and the duration ofdelivery will be increased. By specifying the relative proportions ofsalt and free base forms, the rate and duration of drug delivery may beeffectively controlled to a desired range to optimize its physiologiceffect.

Drugs which are available in an ionic form and can be converted to afree base or neutral form include, but are not limited to: Drug FreeBase - Salt forming group Gleevec pyrimidinyl, piperizinyl Midostaurinamino Cladribine purinyl Clotrimazole imidoxolyl Farglitazar oxazolylEpothilone D thiazolyl Mitoxanthrone amino Rosigitazone amino,pyrindinyl Pioglitazone amino, pyrindinyl Probucol phenolic Dipyridimoleamino, piperidnyl

Other drugs which can be converted to the salt form include thosecontaining the following radicals:

2H-Pyrrolyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Pyridyl, Pyrazinyl,Pyrimidinyl, Pyridazinyl, Indolizinyl, Isoindolyl, Indolyl, Indazolyl,Purinyl¹, 4H-Quinolizinyl, Isoquinolyl, Quinolyl, Phthalazinyl,Naphthyridinyl, Quinoxalinyl, Quinazolinyl, Cinnolinyl, Pteridinyl,4aH-Carbazolyl¹, Carbazolyl¹, β-Carbolinyl, Phenanthridinyl, Acridinyl¹,Perimidinyl, Phenantrholinyl, Phenazinyl, Isothiazolyl, Thiazolyl,Pyrrolidinyl, Pyrrolinyl, Phenothiazinyl, Phenoxazinyl, Imidazolidinyl,Imidazolinyl, Pyrazolidinyl, Piperidyl³, piperazinyl, Indolinyl,Isoindolinyl, Quinuclidinyl, Morpholinyl¹, Purinyl, and Guanidino.

Drugs that are able to exist in either a neutral or conjugate base forminclude those containing the following acid groups: carboxylic acid,sulfonic acid, phosphoric acid, sulfinic acid, and phenolic hydroxyl.

In addition to the general concept of using the salt form and neutralform of a drug, an even greater control of drug elution rate can beobtained by selection of relatively more or less hydrophobic orhydrophilic counter-ions for the ionic or salt form of the drug.

For example, if the drug contains a conjugate base functionality, alkalimetal counter cations (e.g., Li+, Na+, K+) would confer greater watersolubility and faster elution rate than quaternary ammonium countercations (e.g., benzyltrimethylammonium, also known as benzalkonium). Ifthe drug contains a base functionality in the neutral form, protonationby an acid giving a halogen counter anion (e.g., chloride, bromide),would render the ionic form more water soluble and more rapidly elutingthat if the counter anion were a carboxylate anion, particularly a fattyacid carboxylate (e.g., laurate, palmitate, stearate).

Further, it is envisioned that control of the elution rate of the purelyionic form of the drug (no neutral form present) may be obtained by therelative proportions of the ionic drug with a relatively hydrophiliccounter-ion and a relatively hydrophobic, though still water soluble,counter-ion (ether counter-cation or counter-anion depending on theneutral structure of the drug, i.e., whether the neutral drug is an acidor a base).

Additionally, the neutral form of a drug is more hydrophobic than theionic form, so the neutral form will generally have a greater solubilityin the matrix material, such as an organic polymer material, which canbe used to slow the elution rate. Experience has shown that as the totaldrug loading of a water soluble drug is increased, the proportion ofdrug released initially in a so-called burst release is greatlyincreased. It is known that a drug that is soluble in the deliverymatrix will elute more slowly than a drug that is in a separate phase,so a higher loading of drug that can be controlled to be more slowlyeluting can be achieved by increasing the proportion of the neutral,non-ionic drug form.

Implantable Drug Delivery Forms

In the examples herein, the drug may be delivered from reservoirs orholes in an implantable stent. When delivered from a stent, the agentmay be provided in any known polymer, and preferably a biodegradable orbioresorbable polymer. To provide primarily luminal delivery of anagent, the agent deposit is covered with a polymer deposit which acts asa cap and substantially prevents mural delivery. The polymer cap can beformed of a slower degrading polymer than the polymer used with theagent. Alternatively, to provide primarily mural delivery, the agentdeposit can be placed on a polymer deposit which acts as a base andsubstantially prevents luminal delivery.

Many alternatives exist for local delivery of drugs from implantablemedical devices. The stents with holes forming drug delivery reservoirsdescribed above are one example. Other examples include microspheres,microparticles, nanospheres, nanoparticles, implantable osmotic devices,stents or other implants incorporating drug by coating, affixingthreads, microspheres, or sleeves. The implantable device can bemetallic, polymer, or other biocompatible material and can bebio-erodible, permanent, or partially bio-erodible. Each of theseimplantable local drug delivery devices can benefit from the combinationof different forms of the same drug to decrease drug solubility, slowrelease rate, and extended release by using the free-base, soft counterion, or one of the other methods which will be discussed below.

Using an Inclusion Complex

A second method of controlling the water solubility of a morehydrophobic drug is by creating a non-covalent complex of the drug witha more hydrophilic complexation agent. An inclusion complex is a way ofmaking a neutral, hydrophobic drug more water soluble. Such complexesare well known as a method of increasing the water solubility ofhydrophobic drugs, particularly for oral delivery. By selecting theamount of complexation agent such that there is less agent thannecessary to achieve total solubility of all the drug, the ratio of amore water soluble form to a less water soluble form can be controlledand hence the rate of release or elution of drug from a device can bemodulated. Such complexes often occur in integer molar ratios, such as1:1 or 2:1, so that by selection of the amount of complexation agent,the relative proportion of more water soluble to less water soluble drugforms can be controlled.

Complexes of agent and drug can be inclusion complexes, such as formedby cyclodextrin and sulfobutyl cyclodextrin which have a hydrophilicexterior and a hydrophobic interior that can accommodate a hydrophobicdrug to increase its water solubility. Thus, by specifying the relativemolar proportions of drug and cyclodextrin, the relative amounts of fasteluting complexed drug and slow eluting un-complexed drug can becontrolled, which will allow control of the overall release kinetics.Additionally, if a portion of a drug substance can be held in aclathrate structure, that portion of the overall drug dose will bereleased more slowly, thus allowing modulation of the release.

Using Solubilization Agents

A third method of controlling the water solubility of a generallyhydrophobic drug is by the addition of stabilizers, meaning compoundsthat stabilize the amount or concentration of a drug substance in anaqueous based or physiologic solution. Stabilizers can be surfactants,emulsifiers, hydrotropes, etc. Such molecules are often amphiphilic,where one section of the molecule is relatively more hydrophilic andanother section is relatively more hydrophobic. It has been found thatthe maximum solubility of hydrophobic drugs is proportional to theamount of stabilizer present. Consequently, it is envisioned to modulatethe release rate of a hydrophilic drug by specifying the level ofstabilizer at or below the level required for complete solubility. Thus,a portion of the drug dose will be more soluble due to the interactionwith the stabilization agent, which the remaining portion will be lesssoluble based on the structure of the drug. Again, the overall drugrelease rate will be modulated by the level of stabilizer incorporatedinto the overall drug formulation. Example agents envisioned areamphiphilic, ionic and non-ionic agents such as the polysorbates, Tween,and Brij materials, PEO-glycerol-fatty acid esters, and phospho-lipidssuch as phosphoryl choline, DPPC, DPPE, DPP inositol and PEO-PC adducts.

Changing Crystalline Form

A fourth method of controlling the water solubility of a drug iscontrolling the relative proportions of different crystalline forms ofthe drug. For example, some drugs occur in both a less rapidlydissolving crystalline lattice form and a more rapidly dissolvingamorphous form.

This would be most practically accomplished by segregating thecrystalline form into one reservoir or area on the delivery device, andthe amorphous form to another. Although thermodynamically the eventualsolubility of the drug forms is identical, kinetically the drug in theamorphous form will be solubilized more rapidly than that in thecrystalline form, thus allowing modulation of the overall drug releaseprofile.

Some drugs have crystalline forms that contain water of crystallizationand are often more rapidly solubilized into aqueous systems than thesame drug occurring in a second crystalline form not including water ofcrystallization.

A polymorph is just one of the various crystalline lattice forms(“morphologies”) that a drug can exist in. In addition to the “puredrug” crystalline forms, of which there may be several, many drugs canform crystalline forms that include a specific number of solventmolecules in the lattice (such as the water of crystallization in ahydrate form). So, solvates are just like hydrates, except an organicsolvent takes the place of water. Different solvate crystalline forms ofa drug will have both different solubility and different IntrinsicDissolution Rates (IDR's), which will translate into different elutionrates. Thus, solubility can be different for the same drug in differentcrystalline forms, with different anhydrate, or with different solvates.

In the method of the invention, the overall delivery profile can betailored by combining the effects of the excipient/matrix and theeffects of the form of the drug, since the form of the drug affects thewater solubility, lipid solubility, hydrophilic-hydrophobic balance,etc., central to controlling the mobility of the drug. Thehydrophilic-hydrophobic balance of the free base structure, neutralstructure, or conjugate base structure is useful in developing theproportions of neutral (non-ionic) and ionic forms of the drug toachieve a particular desired elution profile. Hydrophobicity may bedetermined experimentally by the oil-water portioning constant (Pow)(larger values are more hydrophobic) or by calculation of the Hansensolubility parameter (lower values are more hydrophobic).

EXAMPLES

The following non-limiting Examples are provided to further illustratethe preferred embodiments of the present invention.

Example 1

In the case of imatinib, the ionic form (Gleevec or imatinib mesylate)is made by reaction with an acid. Conversely, if the neutral form isinherently an acid, the reaction with a base will give the acid form.For imatinib mesylate, which is already in the salt form, the drug isreacted (de-protonated) with a base stronger than imatinib itself, suchas sodium carbonate. The acid will then neutralize—makes the salt of—thestrongest base present.

The following method was followed for preparation of imatinib free basefrom imatinib mesylate salt.

-   -   1) A solution was prepared by combining imatinib mesylate salt,        MW 589.7 g/mole, 5.9 g and water, 100 mL, to make a 0.1 Molar        solution.    -   2) A second solution was prepared by combining sodium carbonate,        MW 106 g/mole, 10.6 g and water, 100 mL, to make a 1.0 Molar        solution.    -   3) A 20 ml vial with screw cap was fitted with a magnetic        stirrer and placed on a stirring plate.    -   4) A 4 mL aliquot of the imatinib mesylate salt, solution, 0.4        mmoles salt, was added to the beaker and stirring begun.    -   5) A 0.5 mL aliquot of the sodium carbonate solution, 0.5 mmoles        Na₂CO₃ (25% molar excess), was added drop-wise to the stirred        solution. imatinib free base precipitated from the solution.    -   6) The vial was sealed with a screw cap and held in a        refrigerator at 2-4 C for 16 hours.    -   7) The vial was removed, then centrifuged for two minutes, and        the clear supernatant decanted from the precipitated white free        base.    -   8) The free base was washed with 10 mL aliquots of ice water,        centrifuged, and the supernatant decanted. The pH of the        supernatant was measured with a pH strip.    -   9) The washing process was repeated until the supernatant was        neutral (pH 7).    -   10) After the last washing step, the precipitated free base was        dried under vacuum (>29 in. Hg) at ambient temperature overnight        to provide imatinib free base as a white powder.

The imatinib free-base (slow release) and the imatinib meslate salt(Gleevec) were loaded into holes in stents in a polymer matrix of PLGA85/15 with a PLGA 85/15 base and cap and the release from the stents wasrecorded in FIG. 1. A solvent such as NMP or anisol was used to depositthe drug/polymer compositions and then evaporated. The releases shown inFIG. 1 are the average of three stents each. Methods and systems fordepositing polymers and drugs within holes in stents are describedfurther in WO 2004/026182 which is incorporated herein by reference.

As shown in FIG. 1, the free base gives the slowest release and the saltprovides the fastest release. The dosage for this example was about 160micrograms normalized for a 16 mm long stent. The free base and saltforms where then combined in the ratios of 86:14, 66:34, and 46:54 andit was shown that the rate of the release (solubility of the drug) isproportional to the percentage of free base or salt. Thus, the selectionof a percentage of free base and salt can be used to provide a selecteddrug release kinetic.

As can be seen in FIG. 1, the release of the salt form alone isessentially complete in about 48 hours. The addition of the free-baseform allows the release to be extended past 48 hours to about 72 hoursfor a formulation of 46% free base and to about 120 hours for aformulation of about 66% free base. While a formulation with 86% freebase continues to release imatinib in-vitro at 168 hours and beyond.

Example 2

The same procedure was repeated for a higher dose of about 270micrograms and the release is shown in FIG. 2. In this example, PLA-PCLwas added to the PLGA base to form a 50/50 mixture while the matrix forthe drug and the cap were PLGA as in Example 1. This example shows asimilar result that the release rate can be slowed by addition of thefree-base form of the drug and the selection of a desired releasekinetic can be achieved by selecting the proportion of free-base tosalt.

Example 3

FIG. 3 illustrates the linearity of the effect of TWEEN 20 on solubilityof paclitaxel. The solubility of the paclitaxel is proportional to theamount of TWEEN 20 included in the formulation. More specifically, thesolubility of paclitaxel increased proportionally to the concentrationof TWEEN 20. Thus, for faster releasing paclitaxel formulations asolubilizing agent, such as TWEEN can be used.

Example 4

FIG. 4 illustrates the effect of several counter ions on the in vitrorelease of a drug, in this example imatinib. Total drug load was 150 μgto 200 μg. PLA-PLC was used in the base and cap while the matrixcontaining the drug was PLGA as in Examples 1 and 2. As plainlyillustrated in the figure, imatinib mesylate achieved a significantlyhigher cumulative release, relatively quickly, than imatinib salicylate,which itself was significantly higher that that of imatinib.

Example 5

FIG. 5 illustrates the effect of changing the molar ratio of a drug, inthis example imatinib, to its salt on the in vitro release of the drug.Again, PLA-PCL was used in the base and cap while the matrix containingthe drug was PLGA. The total drug load was 150 μg. As plainlyillustrated in the figure, lower ratios of imatinib to the salt imatinibascorbate resulted in significantly higher release rates.

While the invention has been described in detail with reference toexemplary embodiments thereof, it will be apparent to one skilled in theart that various changes can be made, and equivalents employed, withoutdeparting from the scope of the invention. The foregoing description ofthe preferred embodiments of the invention has been presented forpurposes of illustration and description. It is not intended to beexhaustive or to limit the invention to the precise form disclosed, andmodifications and variations are possible in light of the aboveteachings or may be acquired from practice of the invention. Theembodiments were chosen and described in order to explain the principlesof the invention and its practical application to enable one skilled inthe art to utilize the invention in various embodiments as are suited tothe particular use contemplated. It is intended that the scope of theinvention be defined by the claims appended hereto, and theirequivalents. The entirety of each of the aforementioned documents isincorporated by reference herein.

1. An implantable drug delivery device comprising: an implantable deviceconfigured to be implanted within tissue, lumens, or organs of the body;a beneficial agent provided in or on the implantable medical device fordelivery to the tissue, lumen, or organ of the body to achieve a desiredbeneficial effect; wherein the beneficial agent is provided in twodifferent forms, a first form having a higher solubility and a secondform having a lower solubility, and wherein the two different forms arepresent in a proportion which is selected to achieve a desired releaserate.
 2. The device of claim 1, wherein the implantable device ismicrospheres, microparticles, nanospheres, or nanoparticles.
 3. Thedevice of claim 1, wherein the implantable device is a metallic implant.4. The device of claim 1, wherein the implantable device is a stent. 5.The device of claim 1, wherein beneficial agent is coated on theimplantable device.
 6. The device of claim 1, wherein the beneficialagent contained in reservoirs in the implantable medical device.
 7. Thedevice of claim 6, wherein the different forms of the beneficial agentare contained in different reservoirs.
 8. The device of claim 6, whereinthe different forms of the beneficial agent are contained in the samereservoir.
 9. The device of claim 1, wherein the first form is a saltform and the second form is a free base form of the agent.
 10. Thedevice of claim 1, wherein the first form is a salt form and the secondform is an acid form.
 11. The device of claim 1, wherein the first formand the second form are different ionic forms of the agent.
 12. Thedevice of claim 1, wherein the first form includes an inclusion complexand the second form includes no inclusion complex or less inclusioncomplex than the first form.
 13. The device of claim 1, wherein thefirst form includes a solubilization agent and the second form includesno solubilization agent or less solubilization agent.
 14. The device ofclaim 1, wherein the first form is a different crystal form, hydrate, orsolvate from the second form.
 15. The device of claim 1, wherein thebeneficial agent is imatinib and the first and second forms arefree-base and salt forms.
 16. A method of forming an implantable drugdelivery device comprising: selecting an implantable device configuredto be implanted within tissue, lumens, or organs of the body; providinga beneficial agent in two different forms, a first form having a highersolubility and a second form having a lower solubility; selecting aproportion of the two different forms to achieve a desired release rate;affixing the beneficial agent in the two different forms and in theselected proportion to the implantable device.
 17. The method of claim16, wherein the two different forms of the beneficial agent are mixedtogether before affixing to the implantable device.
 18. The method ofclaim 16, wherein the two different forms of the beneficial agent aremaintained separate when affixed to the implantable device.
 19. Themethod of claim 16, wherein the implantable device is microspheres,microparticles, nanospheres, or nanoparticles.
 20. The method of claim16, wherein the implantable device is a metallic implant.
 21. The methodof claim 16, wherein the implantable device is a stent.
 22. The methodof claim 16, wherein beneficial agent is coated on the implantabledevice.
 23. The method of claim 16, wherein the beneficial agent iscontained in reservoirs in the implantable medical device.
 24. Themethod of claim 16, wherein the first form is a salt form and the secondform is a free base form of the agent.
 25. The method of claim 16,wherein the first form is a salt form and the second form is an acidform.
 26. The method of claim 16, wherein the first form and the secondform are different ionic forms of the agent.
 27. The method of claim 16,wherein the first form includes an inclusion complex and the second formincludes no inclusion complex or less inclusion complex than the firstform.
 28. The method of claim 16, wherein the first form includes asolubilization agent and the second form includes no solubilizationagent or less solubilization agent.
 29. The method of claim 16, whereinthe first form is a different crystal form, hydrate, or solvate from thesecond form.
 30. The method of claim 16, wherein the beneficial agent isimatinib and the first and second forms are free-base and salt.